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Nonhydrolysable Analogues of (p)ppGpp and (p)ppApp Alarmone Nucleotides as Novel Molecular Tools
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SYSNO ASEP 0545506 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Nonhydrolysable Analogues of (p)ppGpp and (p)ppApp Alarmone Nucleotides as Novel Molecular Tools Tvůrce(i) Mojr, Viktor (UOCHB-X) ORCID
Roghanian, M. (SE)
Tamman, H. (BE)
Do Pham, Duy Dinh (UOCHB-X) ORCID
Petrová, Magdalena (UOCHB-X) RID
Pohl, Radek (UOCHB-X) RID, ORCID
Takada, H. (JP)
Van Nerom, K. (BE)
Ainelo, H. (BE)
Caballero-Montes, J. (BE)
Jimmy, S. (SE)
Garcia-Pino, A. (BE)
Hauryliuk, V. (EE)
Rejman, Dominik (UOCHB-X) RID, ORCIDZdroj.dok. ACS Chemical Biology. - : American Chemical Society - ISSN 1554-8929
Roč. 16, č. 9 (2021), s. 1680-1691Poč.str. 12 s. Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova pppGpp ; pppApp ; nonhydrolysable ; molecular tools Obor OECD Organic chemistry CEP 8F19006 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Způsob publikování Omezený přístup Institucionální podpora UOCHB-X - RVO:61388963 UT WOS 000697343400008 DOI 10.1021/acschembio.1c00398 Anotace While alarmone nucleotides guanosine-3′,5′-bisdiphosphate (ppGpp) and guanosine-5′-triphosphate-3′-diphosphate (pppGpp) are archetypical bacterial second messengers, their adenosine analogues ppApp (adenosine-3′,5′-bisdiphosphate) and pppApp (adenosine-5′-triphosphate-3′-diphosphate) are toxic effectors that abrogate bacterial growth. The alarmones are both synthesized and degraded by the members of the RelA-SpoT Homologue (RSH) enzyme family. Because of the chemical and enzymatic liability of (p)ppGpp and (p)ppApp, these alarmones are prone to degradation during structural biology experiments. To overcome this limitation, we have established an efficient and straightforward procedure for synthesizing nonhydrolysable (p)ppNuNpp analogues starting from 3′-azido-3′-deoxyribonucleotides as key intermediates. To demonstrate the utility of (p)ppGNpp as a molecular tool, we show that (i) as an HD substrate mimic, ppGNpp competes with ppGpp to inhibit the enzymatic activity of human MESH1 Small Alarmone Hyrolase, SAH, and (ii) mimicking the allosteric effects of (p)ppGpp, (p)ppGNpp acts as a positive regulator of the synthetase activity of long ribosome-associated RSHs Rel and RelA. Finally, by solving the structure of the N-terminal domain region (NTD) of T. thermophilus Rel complexed with pppGNpp, we show that as an HD substrate mimic, the analogue serves as a bona fide orthosteric regulator that promotes the same intra-NTD structural rearrangements as the native substrate. Pracoviště Ústav organické chemie a biochemie Kontakt asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Rok sběru 2022 Elektronická adresa https://doi.org/10.1021/acschembio.1c00398
Počet záznamů: 1